Monocyte Functional and Metabolic Re-Programming Induced by Oxidized LDL

Abstract

Background: Dyslipidaemia affects 2 in 3 adult Australians and increases the lifetime risk of atherosclerotic cardiovascular diseases (ASCVDs). The stability of atherosclerotic lesions is associated with macrophage phenotype, with a higher proportion of inflammatory macrophages found in vulnerable plaques. Hypothesizing that monocyte phenotype may influence macrophage phenotype, here we are investigating whether oxidised LDL (oxLDL) reprograms monocytes giving them a persistent heightened inflammatory potential.

Method: Monocytes were exposed to oxLDL for 24hours, washed and rested (from oxLDL) then re-stimulated with LPS (THP-1 cells) or M1 or M2 polarising stimuli (macrophages) for 24hours. The cellular cytokine expression, metabolic profile, redox status and mitochondrial functional parameters were assessed.

Results and Conclusion: oxLDL caused a mixed inflammatory profile, induced lipid accumulation (in THP-1s), and caused a metabolic shift of the cells (both THP-1 and primary human monocytes) towards glycolysis accompanied by a marked mitochondrial dysfunction (decreased mitochondrial respiratory parameters). OxLDL enhanced mitochondrial membrane potential, decreased ROS, NO and mtROS production, reversed complex V activity and possibly de-activated complex I activity. Mitochondrial mass, area and branching were also significantly reduced (THP-1s) by oxLDL. oxLDL-mediated hypoxia-like response or reductive stress was proposed as a mechanism for such effects. The persistent mitochondrial dysfunction induced by oxLDL may lead to dysregulated polarisation of the cells to the M2 macrophage phenotype. In a clinical scenario, the presence of dysfunctional M2 macrophages would heighten necrotic core formation and influence plaque instability. Thereby, we propose that mitigating the oxLDL-induced mitochondrial damage in the monocytes could be a potential way to overcome the subsequent deleterious metabolic changes and thereby rescue macrophage function.